Cancer is a major cause of death worldwide, being the second-leading cause of death in developed countries, and even the number one cause of death in e.g. Australia, Japan, Korea, Singapore and the male population of the United Kingdom and Spain. The number of individuals who develop cancer each year is increasing. This increase in prevalence in cancer is comparable with the increased number of individuals suffering from diabetes. Diabetes is a chronic and serious global health problem and affects millions of people worldwide. Diabetes often results in substantial morbidity and mortality, mainly from cardiovascular complications, eye and kidney diseases and limb amputations. The increase in prevalence of such diseases is attributed to population growth, aging and urbanization. Therefore, there is a need to develop therapeutic agents that target intracellular proteins which can lower the incidence of cancer and diabetes.
One such class of intracellular proteins is the nuclear receptor proteins which include the peroxisome proliferator activated receptors (PPARs). PPARs are ligand activated transcription factors belonging to the nuclear receptor superfamily that includes receptors for steroids, thyroid hormone, vitamin D, and retinoic acid. The functional role of PPARs ranges from modulation of glucose and lipid homeostasis to regulation of cell growth and differentiation. For example, it was established that PPAR-gamma (PPARγ) is a dominant regulator of adipocyte differentiation. The PPARγ can also inhibit the proliferation of malignant cells from different lineages such as breast, prostate, colorectal, non-small cell lung, pancreatic, bladder and gastric carcinoma. For this reason, numerous endogenous ligands for the PPARγ have been synthesized for developing therapeutic agents to target a variety of diseases including diabetes and cancer. For example, drugs such as rosiglitazone (RGZ), troglitazone (TGZ), ciglitazone (CGZ) and pioglitazone (PGZ) are a class of thiazolidinedione (TZD) drugs that selectively bind and activate PPARγ to treat diabetes and other related diseases. However, the main side effect of all thiazolidinediones is significant water retention, leading to edema in some and potentially heart failure in others.
Although further studies have been carried out to identify agents useful for treating diseases and pathological conditions affected by nuclear receptors and the associated co-factors, most of these synthetic ligands exhibit harmful side effects, which have limited their use in the clinic. Therefore, identification of new ligands that have a therapeutic purpose for treating the above diseases is highly desirable.
Accordingly, it is an object of the invention to provide a compound that acts a ligand of the PPARγ receptor.
It is a further object of the invention to provide a compound that can be a potent activator of the PPARγ receptor.
Another object of the invention is to provide a pharmaceutical composition that can ameliorate the disadvantages mentioned above.